Elevated pressure selectively blunts flow‐evoked vasodilatation in rat mesenteric small arteries

Abstract

Background and purpose: The present study investigated mechanisms underlying impaired endothelium-dependent vasodilatation elicited by elevating the intraluminal pressure in rat mesenteric small arteries. Experimental approach: Arterial segments (internal diameter 31672 mm, n ¼ 86) were mounted in a pressure myograph. The effect of elevating pressure from 50 to 120 mmHg for 1 h before resetting it to 50 mmHg was studied on endotheliumdependent vasodilatation. Key results: In arteries constricted with U46619 in the presence of indomethacin, shear stress generated by flow, evoked vasodilatation that was abolished by an inhibitor of nitric oxide (NO) synthase, asymmetric dimethylarginine (1 mM), whereas acetylcholine-induced vasodilatation was unchanged. After elevation of intraluminal pressure for 1 h and then resetting it to 50 mmHg, vasodilatation induced by shear stress and the NO donor, S-nitrosopenicillamine was inhibited, while vasodilatation induced by a guanylyl cyclase activator, BAY 412272, and acetylcholine was unaltered. Superoxide levels sensitive to polyethylene glycol superoxide dismutase were increased in segments exposed to elevated pressure. A superoxide scavenger, tempol (300 mM), a general endothelin receptor antagonist, SB 217242 and the selective ET A receptor antagonist, BQ 123 preserved shear stress-evoked vasodilatation. Conclusions and Implications: The present study shows that transient exposure to an elevated intraluminal pressure selectively inhibits flow-evoked NO-mediated vasodilatation, probably through activation of endothelin receptors and increased formation of superoxide. In contrast, elevation of pressure did not affect the acetylcholine-evoked endotheliumderived hyperpolarizing factor type vasodilatation in mesenteric small arteries.

Effects of Acute Transmural Pressure Elevation on Endothelium-Dependent Vasodilation in Isolated Rat Mesenteric Veins

“…Although it has been suggested that acute increases in TMP in MSAs can impair endothelium-dependent and independent vasodilation [2,3], our results in MSVs indicate the opposite. Differences in the protocols used may account for this discrepancy.…”

“…In pathologic conditions, such as hypertension, there is evidence of increased production of superoxide anions, thus reducing NO bioavailability and impairing endothelium-dependent vasodilation in arteries [4]. Our findings with BK-induced vasodilation at high TMP did not enable us to make further investigations regarding potential mechanisms associated with increasing TMP that could inhibit vasodilation [3,4]. Alternatively, we further investigated possible endothelium-derived factors participating in vasodilation induced by BK in MSVs exposed to acute levels of TMP.…”

“…Previous in vitro studies conducted in pressurized small arteries including MSAs have shown that endothelium-dependent vasodilation [2,3,4,5,9,10] evoked by flow- and receptor-selective agonists is significantly reduced with increases of TMP. Endothelium-independent vasodilation induced by the NO donors, SNP or SNAP, were also reduced by TMP elevation [2,3,4,9]. However, in the present study, the lack of acute pressure effects on BK as well as NO donor-evoked vasodilation suggests that in PGF2α-preconstricted MSVs the activity of endothelial NOS and VSM guanylyl cyclase is not altered.…”

“…50, 80 and 120 mm Hg, on each vessel used. Christensen et al [3] evaluated the effects of elevating TMP from 50 to 120 mm Hg for 1 h before resetting the pressure to 50 mm Hg on vasodilation induced by increased flow, acetylcholine and SNAP. Thus, time-related effects cannot be ruled out as a cause of endothelial dysfunction in these studies.…”

“…The production of vasodilator substances by endothelial cells is triggered primarily by the shear stress of blood flow and receptor-specific activation by agonists such as acetylcholine and bradykinin (BK). Endothelium-dependent vasodilation has been widely investigated in the arteries with some studies showing the presence of endothelium dysfunction in mesenteric small arteries (MSAs) of healthy rats studied in vitro at a high level of transmural pressure (TMP) [2,3]. An impaired endothelial dilator function has also been reported in some disease conditions in arteries [4,5,6,7,8], including studies in rat mesentery [9,10].…”